This invention concerns halogen substituted tetracyclic tetrahydrofuran derivatives having antipsychotic, cardiovascular and gastrokinetic activity and their preparations; it further relates to compositions comprising them, as well as their use as a medicine.
WO 97/38991, published on Oct. 23, 1997, discloses tetracyclic tetrahydrofuran derivatives. WO 96/14320 and WO 96/14321 both disclose isoxazolidine containing tetracyclic derivatives, all having antipsychotic, cardiovascular and gastrokinetic activity.
An article by Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407) describes the synthesis of (xc2x1)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta-[1,2-b]furan-2-methanamine oxalic acid. Said compound was synthesized as potential antidepressant; however, it was found that this particular tetrahydrofurfurylamine derivative was inactive as antidepressant at a dose of 300 mg/kg.
The present compounds differ structurally from the art-known compounds by their specific substitution pattern on the dibenzoazepine ring and the presence of a tetrahydrofuran ring instead of an isoxazolidine ring, and are further distinguished by valuable pharmacological and physicochemical properties.
This invention concerns compounds of formula (I) 
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
n is zero, 1, 2, 3, 4, 5 or 6;
X is CH2 or O;
R1 and R2 each independently are hydrogen, C1-6alkyl, C1-6alkylcarbonyl, halomethylcarbonyl or C1-6alkyl substituted with hydroxy, C1-6alkyloxy, carboxyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl or aryl; or R1 and R2 taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or a radical of formula: 
wherein:
R9, R10, R11 and R12 each independently are hydrogen, halo, halomethyl or C1-6alkyl;
m is zero, 1, 2, or 3;
R13, R14, R15 and R16 each independently are hydrogen, C1-6alkyl, aryl or arylcarbonyl; or
R15 and R16 taken together may form a bivalent radical C4-5alkanediyl;
R17 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, halomethylcarbonyl,
C1-6alkyloxycarbonyl, aryl, di(aryl)methyl or C1-6alkyl substituted with hydroxy,
C1-6alkyloxy, carboxyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl or aryl;
R3 and R4 are both halogen; or
R3 is halogen and R4 is hydrogen; or
R3 is hydrogen and R4 is halogen; and
aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, C1-6alkyl and halomethyl.
In the foregoing definitions C1-6alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl; C4-5alkanediyl defines bivalent straight and branch chained saturated hydrocarbon radicals having from 4 to 5 carbon atoms such as, for example, 1,4-butanediyl, 1,5-pentanediyl; halo is generic to fluoro, chloro, bromo and iodo. The term halomethyl is meant to include mono-, di-, and trihalomethyl. Examples of halomethyl are fluoromethyl, difluoromethyl and particularly trifluoromethyl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating the free base form of the compound of formula (I) with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Particular acid addition salts include hydrochloric acid and [R-(R*,R*)]-2,3-dihydroxy-butanedioic acid (other names are for instance tartaric acid, d-tartaric acid and L-tartaric acid).
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein the nitrogen bearing the R1 and R2 substituents is N-oxidized.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore and hereinafter defines all the possible stereoisomeric forms in which the compounds of formula (I) may exist, thus, also including enantiomers, enantiomeric mixtures and diastereomeric mixtures. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediates as described herein, used to prepare endproducts of formula (I). Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are intended to be encompassed by formula (I).
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term xe2x80x98stereoisomerically pure compounds or intermediatesxe2x80x99 concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms xe2x80x98enantiomerically purexe2x80x99 and xe2x80x98diastereomerically purexe2x80x99 or equivalent terms should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.
The numbering of the tetracyclic ring-system present in the compounds of formula (I), as defined by Chemical Abstracts nomenclature is shown in formula (Ixe2x80x2). 
The compounds of formula (I) have at least three asymmetric centers, namely carbon atom 2, carbon atom 3a and carbon atom 12b. Carbon atoms 3a and 12b are part of an annelated ring system. In this case, where more than 2 asymmetric carbon atoms are present on a ring system, the substituent highest in priority (according to the Cahn-Ingold-Prelog sequence rules) on the reference carbon atom, which is defined as the asymmetric carbon atom having the lowest ring number, is arbitrarily always in the xe2x80x9cxcex1xe2x80x9d position of the mean plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atoms relative to the position of the highest priority substituent on the reference atom is denominated by xe2x80x9cxcex1xe2x80x9d or xe2x80x9cxcex2xe2x80x9d. xe2x80x9cxcex1xe2x80x9d means that the highest priority substituent is on the same side of the mean plane determined by the ring system, and xe2x80x9cxcex2xe2x80x9d means that the highest priority substituent is on the other side of the mean plane determined by the ring system.
Of some compounds of formula (I) and of intermediates used in their preparation, the absolute stereochemical configuration was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration. However, said xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d isomeric forms can be unambiguously characterized by for instance their optical rotation in case xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d have an enantiomeric relationship. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
For example, compound 4 having the stereochemical descriptor A-(2xcex1,3axcex2,12bxcex1) denotes the pure enantiomer having either (a) the [2R-(2xcex1,3axcex2,12bxcex1)] configuration whereby carbon atom 2 is the reference atom having the R configuration and the xe2x80x94CH2xe2x80x94N(CH3)2 substituent is on the xcex1-side of the mean plane, carbon atom 3a has the S configuration because the hydrogen substituent is on the other side of the mean plane relative to the xe2x80x94CH2xe2x80x94N(CH3)2 substituent, and carbon atom 12b has the R configuration because the hydrogen substituent is on the same side of the mean plane relative to the xe2x80x94CH2xe2x80x94N(CH3)2 substituent, or (b) the [2S-(2xcex1,3axcex2,12bxcex1)] configuration whereby carbon atom 2 has the S configuration, carbon atom 3a the R configuration and carbon atom 12b the S configuration.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include the pharmaceutically acceptable addition salts, the stereoisomeric forms, and also the N-oxide forms.
A special group of compounds are those compounds of formula (I) wherein the two hydrogen atoms on carbon atom 3a and 12b are on opposite sides of the mean plane determined by the tetracyclic ring system.
Interesting compounds are those compounds of formula (I) wherein R1 and R2 are each independently hydrogen or C1-6alkyl, or wherein R1 and R2 are taken together with the nitrogen atom to which they are attached, thus forming a morpholinyl ring or a radical of formula (c) or (e); particularly interesting are those compounds of formula (I) wherein R1 and R2 are each independently hydrogen or methyl; more in particular both R1 and R2 are methyl.
Other interesting compounds are those compounds of formula (I) wherein X is CH2.
Still other interesting compounds are those compounds of formula (I) wherein n is 1, 2 or 3, more specifically, n is 1.
Particular compounds are those compounds of formula (I) wherein R3 is hydrogen and R4 is halo, more specifically fluor.
Other particular compounds are those compounds of formula (I) wherein R4 is hydrogen and R3 is halo, more specifically fluor.
Still other particular compounds are those compounds of formula (I) wherein R3 and R4 are both halo, more specifically, both fluor.
Preferred compounds are those compounds of formula (I) wherein the two hydrogen atoms on carbon atom 3a and 12b are on opposite sides of the mean plane determined by the ring system, n is 1 and R1 and R2 are methyl.
Most preferred are 11-fluoro-3,3a,8,12b-tetrahydro-N,N-dimethyl-2H-dibenzo-[3,4:6,7]cyclohepta[1,2-b]furan-2methanamine; the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof, and the N-oxide forms thereof, more in particular, those stereoisomeric forms wherein the two hydrogen atoms on carbon atom 3a and 12b are on opposite sides of the mean plane determined by the ring system such as for instance (xc2x1)-(2xcex1,3axcex2,12bxcex1)-11-fluoro-3,3a,8,12b-tetrahydro-N,N-dimethyl-2H-dibenzo-[3,4:6,7]cyclohepta[1,2-b]furan-2-methanamine and (xc2x1)-(2xcex1,3axcex1,12bxcex2)-11-fluoro-3,3a,8,12b-tetrahydro-N,N-dimethyl-2H-dibenzo-[3,4:6,7]cyclohepta[1,2b]furan-2-methanamine.
The compounds of formula (I) can generally be prepared by N-alkylating an intermediate of formula (II) with an intermediate of formula (III) wherein W is a suitable leaving group such as halo. In the intermediates (II) and (III), R1 to R4, n and X are as defined in the compounds of formula (I). Said N-alkylation can conveniently be carried out in a reaction-inert solvent such as, for example, methanol, tetrahydrofuran, methylisobutyl ketone, N,N-dimethylformamide or dimethylsulfoxide, and optionally in the presence of a suitable base. Stirring and elevated temperatures, for instance reflux temperature, may enhance the rate of the reaction. Alternatively, said N-alkylation may also be performed using the procedure described by Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407) which involves the use of a pressurised reaction vessel. 
The compounds of formula (I) may also be converted into each other following art-known transformation reactions.
In addition, the compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid respectively with a suitable chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The intermediates mentioned hereinabove are either commercially available or may be made following art-known procedures. For instance, intermediates of formula (III) may be prepared according to the procedure described by Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407).
Alternatively, intermediates of formula (III) wherein n is 1, said intermediates being represented by formula (III-a), can also be prepared by reacting an epoxide derivative of formula (IV) with a Grignard reagent of formula (V) wherein Y suitably is halo, thus forming an intermediate of formula (VI) which may subsequently be cyclized according to art-known methods such as the one described in Monkovic et al. 
Epoxides of formula (IV) can be prepared using art-known procedures such as peroxidating an intermediate of formula (VII) with a suitable peroxide such as m-chloroperbenzoic acid. 
The compounds of the present invention show affinity for 5-HT2 receptors, particularly for 5-HT2A and 5-HT2C receptors (nomenclature as described by D. Hoyer in xe2x80x9cSerotonin (5-HT) in neurologic and psychiatric disordersxe2x80x9d edited by M. D. Ferrari and published in 1994 by the Boerhaave Commission of the University of Leiden). The serotonin antagonistic properties of the present compounds may be demonstrated by their inhibitory effect in the xe2x80x9c5-hydroxytryptophan Test on Ratsxe2x80x9d which is described in Drug Dev. Res., 13, 237-244 (1988). Furthermore, the compounds of the present invention show interesting pharmacological activity in the xe2x80x9cmCPP Test on Ratsxe2x80x9d which is described hereinafter, and in the xe2x80x9cCombined Apomorphine, Tryptamine, Norepinephrine (ATN) Test on Ratsxe2x80x9d which is described in Arch. Int. Pharmacodyn, 227, 238-253 (1977).
The compounds of the present invention have favourable physicochemical properties. For instance, they are chemically stable compounds, in particular when compared to the compounds disclosed in WO 96/14320 and WO 96/14321. The compounds of the present invention also have a fast onset of action.
In view of these pharmacological and physicochemical properties, the compounds of formula (I) are useful as therapeutic agents in the treatment or the prevention of central nervous system disorders like anxiety, depression and mild depression, bipolar disorders, sleep- and sexual disorders, psychosis, borderline psychosis, schizophrenia, migraine, personality disorders or obsessive-compulsive disorders, social phobias or panic attacks, organic mental disorders, mental disorders in children, aggression, memory disorders and attitude disorders in older people, addiction, obesity, bulimia and similar disorders. In particular, the present compounds may be used as anxiolytics, antipsychotics, antidepressants, anti-migraine agents and as agents having the potential to overrule the addictive properties of drugs of abuse.
The compounds of formula (I) may also be used as therapeutic agents in the treatment of motoric disorders. It may be advantageous to use the present compounds in combination with classical therapeutic agents for such disorders.
The compounds of formula (I) may also serve in the treatment or the prevention of damage to the nervous system caused by trauma, stroke, neurodegenerative illnesses and the like; cardiovascular disorders like high blood pressure, thrombosis, stroke, and the like; and gastrointestinal disorders like dysfunction of the motility of the gastrointestinal system and the like.
In view of the above uses of the compounds of formula (I), it follows that the present invention also provides a method of treating warm-blooded animals suffering from such diseases, said method comprising the systemic administration of a therapeutic amount of a compound of formula (I) effective in treating the above described disorders, in particular, in treating anxiety, psychosis, schizophrenia, depression, migraine, sleep disorders and addictive properties of drugs of abuse.
The present invention thus also relates to compounds of formula (I) as defined hereinabove for use as a medicine, in particular, the compounds of formula (I) may be used for the manufacture of a medicament for treating anxiety, psychosis, schizophrenia, depression, migraine, sleep disorders and addictive properties of drugs of abuse.
Those of skill in the treatment of such diseases could determine the effective therapeutic daily amount from the test results presented hereinafter. An effective therapeutic daily amount would be from about 0.01 mg/kg to about 10 mg/kg body weight, more preferably from about 0.05 mg/kg to about 1 mg/kg body weight.
For ease of administration, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Acid or base addition salts of compounds of formula (I) due to their increased water solubility over the corresponding base or acid form, are more suitable in the preparation of aqueous compositions.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclo-dextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-xcex2-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions.
Other convenient ways to enhance the solubility of the compounds of the present invention in pharmaceutical compositions are described in WO 97/44014.
More in particular, the present compounds may be formulated in a pharmaceutical composition comprising a therapeutically effective amount of particles consisting of a solid dispersion comprising
(a) a compound of formula (I), and
(b) one or more pharmaceutically acceptable water-soluble polymers.
The term xe2x80x9ca solid dispersionxe2x80x9d defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermo-dynamics, such a solid dispersion is referred to as xe2x80x9ca solid solutionxe2x80x9d. Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.
The term xe2x80x9ca solid dispersionxe2x80x9d also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
The water-soluble polymer in the particles is a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20xc2x0 C. solution.
Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
The particles as defined hereinabove can be prepared by first preparing a solid dispersion of the components, and then optionally grinding or milling that dispersion. Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation, melt-extrusion being preferred.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The following examples are intended to illustrate and not to limit the scope of the present invention.
Experimental Part
A. Preparation of the Intermediate Compounds